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Sex-dependent interactions between leptin, wasting and humoral immunity in two ethnic communities of school-aged children differentially exposed to Schistosoma haematobium

Sex-dependent interactions between leptin, wasting and humoral immunity in two ethnic communities... Abstract Background Leptin is a nutritional hormone whose production is generally higher in females. We investigated how leptin is associated with sex dimorphism during urinary schistosomiasis in relation with wasting. Methods A cross-sectional study was carried out in three villages in northern Senegal. Ninety-eight school-aged children belonging to the Fulani or Wolof villages were enrolled. We performed parasitic diagnosis and anthropometric measurement to evaluate nutritional status. We collected peripheral blood to determine the amount of circulating leptin and immunoglobulin G (IgG), IgG4 and IgE directed to soluble worm antigen preparation (SWAP). Results The prevalence of Schistosoma haematobium infection was higher among boys regardless of ethnic group, but exposure to parasites did not exacerbate malnutrition. The greater ability of girls to produce leptin was not altered by schistosomiasis and was recovered in both ethnic groups. However, while the usual correlation between leptin and fat storage was preserved in Fulani girls, it was disrupted in Fulani boys, who displayed a remarkable susceptibility for wasting. Finally, we observed that leptin was negatively associated with the level of antibodies in Wolof boys. Conclusions Leptin can be disconnected from body fat and may exert a sex-dependent influence on host immune response to S. haematobium infection in Senegalese children. Antibody response, Ethnicity, Leptin, Schistosomiasis, Sex, Wasting Introduction Schistosomiasis is among the most widespread human parasitic diseases, with more than 200 million people infected worldwide and the majority of these infections occurring in sub-Saharan Africa. The two major species are Schistosoma mansoni and Schistosoma haematobium, causing intestinal and urinary schistosomiasis, respectively. Infections with Schistosoma worms have been associated with anaemia, poor nutritional status, cognitive impairment leading to school delays and a decrease in physical fitness.1 A sex-dependent immune profile is observed in Schistosoma-infected adults.2,3 In line with this, a body of evidence suggests that intrinsic host factors may influence susceptibility to infections with parasitic worms according to the host’s sex.4 There is also convincing evidence that the level of malnutrition in children is commonly worse in boys compared with girls,5,6 although others have found similar levels of malnutrition among males and females.7 The extent to which nutritional hormones may mediate sex dimorphism should be considered in order to provide the basis of a link among sex-related infection, malnutrition and immunity. Among the hormones that could be implicated in the crosstalk between sex and nutritional status, the level of serum leptin is consistently higher in girls than boys.8 Leptin is an adipocytokine encoded by the ob gene and is produced by the white adipose tissue. This hormone is a key mediator of energy metabolism and regulates the hypothalamic axis of satiety.9 Its circulating levels are consequently closely related to weight and nutritional disruption. Leptin is also a pro-inflammatory molecule that drives T helper 1 (Th1)-type immunity and impedes the development of the Th2 phenotype.10 Nevertheless, the possibility that leptin mediates immune deficiency during starvation lacks consensus.11,12 To our knowledge, the leptin profile during human schistosomiasis has never been documented. We decided to decipher the sex-dependent regulation of plasma leptin during S. haematobium infection in relation to undernutrition and whether the nutritional hormone is associated with an altered development of host immunoglobulin G (IgG) and IgE antibodies to worm antigens in two rural ethnic groups of school-aged children living in northern Senegal. Materials and methods Study design This cross-sectional study was carried out in October 2011 in three villages of the Podor district located in northern Senegal: Agniam Towguel, Fanaye-Diery and Niandane. Other detailed information regarding the villages has been described elsewhere.13 A total of 125 children from a subcohort of the ‘AnoPalAnoVac’ project (ClinicalTrials.gov, NCT01545115) were initially selected on the basis of their age (6–10 y in October 2011). Ninety-eight children were finally enrolled in the present study. Date of birth was ascertained from vaccination cards or school registers. A standardized questionnaire was completed for each child to collect information on water contact, symptoms of urinary schistosomiasis or previous praziquantel treatment. Children with a malaria episode or haemoglobin <7 g/dL were not included in the cohort for blood collection. Parasitic diagnosis In a preliminary investigation (phase A, see supplementary Table 1), both urine and stool samples were collected from 97 and 95 children, respectively. From each urine sample, 10 mL were filtered and the number of S. haematobium eggs was evaluated by microscopy. S. mansoni infection was detected by the Kato–Katz method using stool samples. Phase B of the study was designed to collect blood for immune analysis. Thirty-eight S. haematobium–infected and 38 uninfected children were included in this second phase of our investigation in which a second stool sample analysis using the Kato–Katz method was performed on S. mansoni–negative children to make sure they are not infected with either form of schistosomiasis. In Niandane, some children have been treated with praziquantel in the last 6 months because this village was included in a national campaign (Supplementary Figure 1). At the end of the current study, all children were dewormed with mebendazole and those found to be positive for schistosomiasis were treated with praziquantel (40 mg/kg body weight). Malaria infection was estimated by microscopic examination of thick blood smears. Serological analysis For analysis of specific antibodies, 3–5 mL of venous blood were collected in heparinized tubes (Becton Dickinson) around noon. Plasma samples were kept at −20°C as 0.15 mL aliquots in 96-well 0.8 mL deep-well storage plates (ABgene, Thermo Scientific, Waltham, MA, USA) until analysis. The serological level of IgG, IgG4 and IgE antibodies to soluble worm antigen preparation (SWAP) from S. mansoni (provided by Mike Doerhoff, University of Nottingham) was evaluated by an in-house enzyme-linked immunosorbent assay (ELISA). Microtitre plates (Nunc, Roskilde, Denmark) were coated with SWAP at a concentration of 5 μg/mL in phosphate-buffered saline (PBS, pH 7.4) and incubated for 2.5 h at 37°C. Plates were then saturated with PBS containing 0.5% gelatin (Merck, Darmstadt, Germany). The sera were diluted to 1/1200 in PBS containing 0.1% Tween-20 for detection of specific IgG and incubated overnight at 4°C. For the detection of anti-SWAP IgG4 or IgE antibodies, sera were diluted to 1:20 in buffer before incubation. Each corresponding biotinylated monoclonal antibody to human Ig isotype (BD Pharmingen, Erembodegem, Belgium) was incubated for 1 h 30 min at 37°C at a 1/2000 dilution for IgG, 1/3000 for IgG4 and 1/1500 for IgE detection. Peroxidase-conjugated streptavidin was then added (Amersham, Les Ulis, France) and colorimetric development was performed with ABTS (2,2′-azino-bis[3-ethylbenzthiazoline-6-sulphonic acid]; Sigma, St. Louis, MO, USA) in 50 mM citrate buffer (pH 4). The absorbance (optical density [OD]) was measured at 405 nm. Individual results were expressed as the ΔOD value: ΔOD=ODx−ODn, where ODx represents the individual OD value in the sera from children and ODn is the mean OD value obtained from a pool of negative controls. The plasmatic concentration of leptin was assayed using a commercial ELISA (R&D Systems, Abingdon, UK) and absorbance read at 450 nm. All ELISA plates were run on an automated washer (ELx405 Select; Biotek, Winooski, VT, USA) and read on an ELx808 microplate reader (Biotek). Anthropometric measurements Anthropometric data were collected by two trained measurers. Weight measurements were recorded using an electronic scale to the nearest 100 g (Tefal, Paris, France). Height measurements were taken twice and the mean value was used for the analysis. Child nutritional indicators, including height for age Z-score (HAZ), weight for age Z-score (WAZ) and body mass index (BMI) for age Z-score (BAZ), were calculated according to the World Health Organization (WHO) 2007 growth standard by using AnthroPlus for children ≥60 months. As this software derives nutritional status information up to 10 years old for WAZ, this indicator was lacking for four children slightly older than 10 y. We used HAZ<−2 to define stunting or chronic malnutrition, WAZ <−2 to define underweight or global malnutrition and BAZ<−2 to define wasting or acute malnutrition. Statistics The mean differences between groups were tested by the Mann–Whitney U-test and χ2 tests were used for categorical variables to compare proportions between groups. Spearman’s rank correlation coefficient was used to check correlation. The Kruskal–Wallis test followed by Dunn’s analysis was used to compare differences among more than two groups, as indicated in the text. All p-values were two-tailed and differences were considered significant for p<0.05. Analyses were performed using GraphPad Prism 5.02 for Microsoft Windows (GraphPad Software, La Jolla, CA, USA). For the multivariate analysis, egg count was transformed into a categorical variable (0, 1 ; 20, ≥20). A logistic regression for ordinal response was used to identify independent predictors of egg count; pairwise interactions were included in the model but none were significant. The proportional odds assumption and log-linearity assumption were verified. Results A total of 98 children ranging in age from 6 to 10 y and living in three different villages in the Senegal River Basin were recruited. The characteristics of the whole population are shown in Table 1. Most of the people living in Niandane belong to the Wolof ethnic group while the populations of Agniam and Fanaye are mainly of Fulani ethnicity. Table 1. Characteristics of the children . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni NS: not significant. aDifferences in the proportion between villages using the χ2 test or mean difference between villages using the Kruskal–Wallis test. Table 1. Characteristics of the children . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni NS: not significant. aDifferences in the proportion between villages using the χ2 test or mean difference between villages using the Kruskal–Wallis test. Schistosoma infection and sex The overall prevalence of urinary schistosomiasis in terms of the presence of eggs in urine samples was 51.6% in children (Figure 1A). Nearly all children were infected in Niandane (92.1% [n=38]), half of them in Agniam (52.9% [n=17]), while a low prevalence was observed in Fanaye (14.3% [n=42]). In Niandane, three children were co-infected with S. mansoni and one child who tested negative for urinary schistosomiasis was infected with S. mansoni (Table 1). In Fanaye, one child was solely infected by S. mansoni, whereas one Ascaris-infected child negative for schistosomiasis was detected in Agniam. Children were commonly infected with the gastrointestinal protozoa parasite Blastocystis sp.13 but negative for malaria infection. When we categorized schistosomal infection intensity as recommended by the WHO, 20% of children were heavily infected (≥50 eggs/10 mL of urine) in Niandane (mean egg number±SD: 52.0±72.8 [n=35]) as opposed to Fulani villages where infected children displayed a light infection intensity (mean egg number±SD: 13.9±10.4 [n=15]). Nevertheless, there were no statistical differences in the egg burdens between villages (Figure 1B). We can infer that in all likelihood, both greater exposure to the source of contaminated water or a child’s high-risk behaviour were responsible to the differential susceptibility to schistosomiasis (Supplementary Figure 2). For example, there was little access to tap water in Niandane and nearly every Wolof child regularly bathed in irrigation canals or in the river. In contrast, in Fanaye, tap water is available and the river is 1.6 km from the village. Figure 1. Open in new tabDownload slide Analysis of (A) the proportion of S. haematobium–infected children and (B) the egg number detected in urine samples according to village and sex. The number of children is indicated below the figures. In (B), six children from Niandane displayed >200 eggs/10 mL urine. The χ2 test was used to evaluate p-values for proportions (A) and the Mann–Whitney U-test to compare egg counts (B). Figure 1. Open in new tabDownload slide Analysis of (A) the proportion of S. haematobium–infected children and (B) the egg number detected in urine samples according to village and sex. The number of children is indicated below the figures. In (B), six children from Niandane displayed >200 eggs/10 mL urine. The χ2 test was used to evaluate p-values for proportions (A) and the Mann–Whitney U-test to compare egg counts (B). We next considered the risk of sex-dependent parasite transmission after stratification by ethnic groups, which also contributes to distinguish areas of mild (Niandane) and low intensity of infection (Fanaye and Agniam). A trend towards a higher proportion of S. haematobium infection among boys as compared with girls was observed in both the Wolof and Fulani populations, although this did not achieve statistical significance (Figure 1A). However, the mean egg burden/10 mL of urine displayed a similar distribution between boys and girls with schistosomiasis in all villages (Figure 1B). On the basis of these results, we confirm that male sex could be a determinant of transmission risk in Senegalese children while the intensity of infection was sex independent in our study. Nutritional characteristics We assessed nutritional status in children stratified by ethnic group and sex (Table 2). Fulani and Wolof living places were not statistically different with respect to nutritional status. Moreover, we found that the proportion of wasting was worsened and three times higher among Fulani boys (58.6%) as compared with Fulani girls (19.4%; p=0.0018). Conversely, the proportion of wasting among Wolof children living in Niandane did not vary statistically between boys (23.8%) and girls (35.3%; p=0.4376) and both presented a similar mean BAZ. Table 2. Children’s nutritional characteristics . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS aDifference between boys and girls using the Mann–Whitney U-test. bDifference as compared with Fulani boys using the Mann–Whitney U-test. cDifference as compared with Fulani girls using the Mann–Whitney U-test. dp<0.05 when compared with Fulani boys using the χ2 test. Table 2. Children’s nutritional characteristics . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS aDifference between boys and girls using the Mann–Whitney U-test. bDifference as compared with Fulani boys using the Mann–Whitney U-test. cDifference as compared with Fulani girls using the Mann–Whitney U-test. dp<0.05 when compared with Fulani boys using the χ2 test. We next investigated the relationships between leptin and wasting in our population. As indicated in Table 2, the average concentration of leptin was strongly and significantly lower in boys as compared with girls in both ethnic groups. The amount of serological leptin was well correlated with BAZ in girls but not in boys in the entire population (Figure 2A and B). This sex-relative positive association was particularly more pronounced among Fulani girls (Figure 2D) compared with Fulani boys (Figure 2C), whose level of the nutritional hormone was consistently low regardless of their nutritional status (data not shown). Therefore the clear sex-dependent exacerbation of acute weight loss among boys belonging to Fulani villages was associated with a strong disruption in the link between weight and leptin level. Figure 2. Open in new tabDownload slide Correlation between plasma leptin concentration and BAZ for all villages (A and B; n=36 and n=24, respectively), Fulani villages (C and D; n=25 and n=16, respectively) and the Wolof village (E and F; n=11 and n=8, respectively) among girls and boys as indicated in the figure. The coefficients of correlation and p-values are indicated when significant. The Spearman’s rank correlation coefficient was used to assess correlation. p-Values <0.05 were considered significant. Figure 2. Open in new tabDownload slide Correlation between plasma leptin concentration and BAZ for all villages (A and B; n=36 and n=24, respectively), Fulani villages (C and D; n=25 and n=16, respectively) and the Wolof village (E and F; n=11 and n=8, respectively) among girls and boys as indicated in the figure. The coefficients of correlation and p-values are indicated when significant. The Spearman’s rank correlation coefficient was used to assess correlation. p-Values <0.05 were considered significant. Malnutrition in relation with Schistosoma infection The proportion of stunting, underweight and wasting did not differ between uninfected and Schistosoma-infected children when they were analysed as a whole (data not shown). As nearly all children were infected in Niandane, we then focused our investigation on the relationships between the number of eggs and nutritional parameters in the whole population of Fulani villages that combined both uninfected and Schistosoma-infected children. We found no correlation between mean egg counts and BAZ in both boys (Spearman r=−0.0513, p=0.7916, n=29) and girls (Spearman r=0.0209, p=0.9127, n=30). In contrast, we found that the amount of circulating leptin was positively associated with egg load in Fulani girls (Spearman r=0.5400, p=0.0308, n=16). This correlation was lacking in both Fulani boys (Spearman r=0.1277, p=0.5429, n=25) and among chronically-infected children from Niandane (data not shown). A multivariate analysis was additionally performed to better evaluate the relationships between egg numbers, nutritional status and circulating leptin (Table 3). We confirmed that the village of Niandane and increased leptin concentration can be considered as risk factors for having higher egg numbers. Overall, our data do not support that S. haematobium infection is associated with weight loss in our cohort of Senegalese children. Table 3. Multivariate analysis for evaluating risk factors associated with egg numbers Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 ap-Values <0.05 indicate a significant difference. Table 3. Multivariate analysis for evaluating risk factors associated with egg numbers Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 ap-Values <0.05 indicate a significant difference. Influence of nutritional status on immune responsiveness to Schistosoma antigens We analysed the antibody response to worm antigens in children. As anticipated because of their greater exposure to S. haematobium infection, Wolof children living in Niandane produced a higher mean level of anti-SWAP-specific antibodies than infected Fulani children for all tested isotypes (Figure 3A–C). Even if the level of anti-SWAP IgG antibodies was statistically slightly increased in uninfected girls as compared with uninfected boys, no difference in the amount of specific antibodies was observed between Schistosoma-infected boys and Schistosoma-infected girls (Figure 3D–F). Figure 3. Open in new tabDownload slide Analysis of circulating antibodies against SWAP antigens among S. haematobium–infected (Sh+) or uninfected children (Sh−). Individual’s IgG, IgG4 and IgE responses are shown according to ethnic places (A, B, C) or sex (D, E, F). Thin lines indicate the mean ΔOD. In the Wolof village (Niandane), since the great majority of children were infected, only results from S. haematobium–infected children are shown. The number of children is indicated below the dot plots. The Mann–Whitney U-test was used to evaluate p-values for statistical significance between two groups. *Significant difference when compared with Sh− children; **significant difference when compared with Sh+ children; ***significant difference between uninfected girls and boys. Figure 3. Open in new tabDownload slide Analysis of circulating antibodies against SWAP antigens among S. haematobium–infected (Sh+) or uninfected children (Sh−). Individual’s IgG, IgG4 and IgE responses are shown according to ethnic places (A, B, C) or sex (D, E, F). Thin lines indicate the mean ΔOD. In the Wolof village (Niandane), since the great majority of children were infected, only results from S. haematobium–infected children are shown. The number of children is indicated below the dot plots. The Mann–Whitney U-test was used to evaluate p-values for statistical significance between two groups. *Significant difference when compared with Sh− children; **significant difference when compared with Sh+ children; ***significant difference between uninfected girls and boys. We next assessed whether BAZ and leptin could be associated with variations in humoral immunity to worm infection in children. Because IgE response was not much higher than the baseline serum IgE observed in uninfected children among the Fulani population, we did not further study its relation with nutritional indicators. Table 4 underlines a significant positive association between SWAP-specific IgG antibodies and BAZ among infected Fulani children. A sex-dependent association was observed between BAZ and the level of SWAP-specific IgG4 but we remain cautious about this sex difference because of the low specific IgG4 concentration detected among girls from Fulani villages (four of them displayed an undetectable IgG4 response). More striking results were observed among infected Wolof boys, whose leptin levels seemed to be strongly and negatively associated with the development of antibodies to worm antigens among IgG, IgG4 and to a lesser extent IgE isotypes (p=0.0556; Table 4). Altogether, these results suggest that the nutritional pattern may sex-dependently influence humoral immunity to Schistosoma infection. Table 4. Correlations between nutritional parameters and humoral immunity in infected children Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 NS: not significant. aNon-parametric Spearman’s rank correlation test. Table 4. Correlations between nutritional parameters and humoral immunity in infected children Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 NS: not significant. aNon-parametric Spearman’s rank correlation test. Discussion Schistosomiasis and malnutrition are overlapping in developing countries and both are public health issues. The present work studied how leptin interacts with wasting in children with urinary schistosomiasis in two ethnic communities of Senegalese school-aged children living near the Senegal River. Our data reveal the presence of complex sex-dependent links between nutritional parameters, living places and the development of acquired immunity to Schistosoma antigens. Several studies in Africa have highlighted the contribution of schistosomiasis to the risk of undernutrition in children,6,14 however, these associations have not been consistently observed.15 In Ethiopia, Mekonnen et al.16 documented that infection with S. mansoni was negatively associated with wasting in people 6–18 y of age. Herein, in a younger population, we did not observe that the odds of infection with S. haematobium exert an apparent effect on nutritional status. The number of children in our cohort is quite low and might explain such discrepancies with other works. However, as discussed by Mekonnen et al.,16 harbouring polyparasite infections should be detrimental for childhood growth and development.17 In our cohort in northern Senegal, the absence of filarial infections (no microfilariae detected in blood smears) or soil-transmitted helminthiasis and hookworms in stool underlines a low level of co-infection that could explain the lack of a deleterious effect of schistosomiasis on weight. In addition, sanitary conditions were different between villages and may be responsible for the levels of exposure to Schistosoma worms observed in our work. The educational background can also accentuate the severity of egg burden,18 and we cannot clearly determine whether knowledge about Schistosoma infection delineated differences in the prevalence of the disease between villages. We nevertheless confirmed that sex was significantly associated with Schistosoma infection in school-aged children. Indeed, the overall increased number of S. haematobium–infected males in the studied villages corroborates previous observations in Senegal19 and other African countries.20,21 Indeed, although we must be cautious since our survey did not tightly capture the social and ecological environment of the population, a number of indications have shown that sex-related differences in the distribution of schistosomiasis infection are attributable to social and cultural habits, where water is obtained and variations in cercarial exposure.19,20,22 Additional work also performed in northern Senegal indicated the level of exposure to contaminated water was not related to the intensity of intestinal infection.23 Beyond these statements, the pattern of stronger resistance to schistosomiasis infection among Senegalese girls, which equally occurred in both Fulani and Wolof populations, did stress that being female, combined with extrinsic environmental factors, might cause a difference in susceptibility to worm infection. It is also well accepted that girls generally demonstrate a better nutritional pattern than boys, at least at younger ages.6,24 We further found that the prevalence of wasting was increased in boys, but only in Fulani children, suggesting that ethnic background could have implications for the outcomes of sex-dependent malnutrition. Nonetheless, although ethnic differences in adiposity have been previously observed in a comparative study,25 the difference in the level of wasting between Fulani and Wolof boys must be interpreted with caution, as Fula are known to be taller and slimmer than many of their neighbouring communities. A variation in physical activity, energy expenditure or in dietary intake between boys and girls may additionally account for the higher level of malnourished boys in Fulani villages. It is indeed important to note that our study was performed during the lean season, when low availability of food is generally characterized by a loss of weight, especially among boys.26 In line with this, it could be argued that Senegalese Fulani boys are highly sensitive to environmental insults that may result in worsened acute weight loss as compared with girls. In addition, the usual correlation between leptin and BAZ was disrupted in Wolof children and was sex dependent in Fulani children. The lack of significant correlations between leptin and anthropometric measurements underlines that leptin is not solely a readout of fat stores and that dissociation between circulating leptin and BAZ could likely be a characteristic of a starvation program to adjust energy intake during food shortages or infections.27 It is actually conceivable that leptin could emerge as a main candidate driving sex differences in the susceptibility to parasite infection. It should be noted that experimental infection with intestinal helminths may modulate leptin levels and that leptin signalling can affect resistance to amoebiasis in children.28 In mice infected with S. mansoni, leptin has been indirectly involved in the outcome of hepatic fibrogenesis.29 However, leptin has been poorly investigated in humans with respect to infection in resource-limited areas and, to our knowledge, its role has never been assessed among schistosomiasis-infected patients. We found that ethnicity and schistosomiasis did not influence the well-known ability of girls to produce a greater amount of leptin than boys. Moreover, we found that circulating leptin was significantly linked with egg burden in urine, but a close association between leptin and worm fecundity has not yet been formally demonstrated. Indeed, one limit of our work concerns the two different ethnic communities under study who were differentially exposed to urinary schistosomiasis. As a result, it is difficult to draw any confident conclusion on the ethnic-dependent interactions between different variables. Therefore we cannot assert whether leptin in relation to host immunity potentiates resistance to this parasitic infection. We and others have reported that nutritional deprivation can alter development of the immune response and thereby may confer higher susceptibility to infections.30–32 While the influence of leptin on inflammation and T-cell activation has often been reported,10 few research teams have addressed the role of adipokines on the development of humoral immunity in humans. Although leptin did not consistently sustain the development of specific antibodies to vaccines,11 a recent study has suggested that leptin enhanced humoral immunity to T-cell-dependent antigens during cholera in humans.33 Herein we did not provide strong evidence that wasting negatively affects humoral immunity in Schistosoma-infected children. However, we observed that an increase in leptin concentration seems to reduce the magnitude of antibody response directed towards SWAP antigens in Wolof boys. It is important to note that the disruption between leptin and BAZ in this population strongly indicates that the potent negative effect of leptin on host immunity was independent of fat stores. Taking into account that a sex-dependent modulation of antibody production to Schistosoma species has previously been documented in endemic areas,2,3 our results substantially suggest that leptin may mediate such variations in populations exposed to the infection. Conclusion Our work suggests the complexity of the loop by which the appetite-regulating hormone leptin is engaged in modulating energy balance and adaptive humoral immune response through mechanisms that are probably independent of the child’s weight. Thus some of the sex-related differences observed in diverse endemic fields could be attributed to the underlying interactions between diet, adipokines, seasonal environment and ethnic background during host–parasite relationships. Their influence on the course of schistosomiasis disease remains an important issue to be further clarified. It may be particularly valuable to conduct a study with a multidisciplinary approach in a larger cohort of children to further assess whether leptin could be a critical factor for susceptibility to parasite infections and sex-dependent fitness in sub-Saharan Africa. Supplementary data Supplementary data are available at Transactions online (http://trstmh.oxfordjournals.org/). Authors’ contributions: EH, GR and LG conceived and designed the field study. AS, SS, MS and LG contributed to field activities and clinical examination. AMS, DDG and LB contributed to parasitic diagnostic tests and did the data analysis. PSS, CB and AMS carried out the ELISAs and did the data analysis. EH analysed the data and wrote the manuscript. GR supervised the work. All authors read and approved the final version of the manuscript. EH is the guarantor of the paper. Acknowledgements: We thank Dr Claire Pincon (Faculty of Pharmacy, Lille, France) for her help with the linear regression analysis. We would like to thank the children, families and health care staffs in the visited villages for their kind collaboration as well as the whole EPLS team for their help with the field study. Funding: LG received support from the Region Nord-Pas de Calais and the Pasteur Institute of Lille. EPLS supported the field investigations while the CIIL provided support for immunological assays. Competing interests: none declared. Ethical approval: Oral and written informed consents were obtained from the parents or the legal guardians of the children in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The present study was approved by the National Ethics Committee of the Ministry of Health of Senegal (September 2011; protocol number SEN11/43). This work has been carried out as part of the ‘SchistoVAN’ project and is registered with ClinicalTrials.gov (NCT01553552). References 1 Colley DG , Bustinduy AL, Secor WE, et al. . Human schistosomiasis . Lancet 2014 ; 383 ( 9936 ): 2253 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Remoue F , Rogerie F, Gallissot MC, et al. . Sex-dependent neutralizing humoral response to Schistosoma mansoni 28GST antigen in infected human populations . J Infect Dis 2000 ; 181 ( 5 ): 1855 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Webster M , Libranda-Ramirez BD, Aligui GD, et al. . 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Prevalence of malnutrition among settled pastoral Fulani children in southwest Nigeria . BMC Res Notes 2008 ; 1 : 7 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Horlick MB , Rosenbaum M, Nicolson M, et al. . Effect of puberty on the relationship between circulating leptin and body composition . J Clin Endocrinol Metab 2000 ; 85 ( 7 ): 2509 – 18 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 9 Tilg H , Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity . Nat Rev Immunol 2006 ; 6 ( 10 ): 772 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Naylor C , Petri WA Jr. Leptin regulation of immune responses . Trends Mol Med 2016 ; 22 ( 2 ): 88 – 98 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Moore SE , Morgan G, Collinson AC, et al. . Leptin, malnutrition, and immune response in rural Gambian children . Arch Dis Child 2002 ; 87 ( 3 ): 192 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Palacio A , Lopez M, Perez-Bravo F, et al. . Leptin levels are associated with immune response in malnourished infants . J Clin Endocrinol Metab 2002 ; 87 ( 7 ): 3040 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 13 El Safadi D , Gaayeb L, Meloni D, et al. . Children of Senegal River Basin show the highest prevalence of Blastocystis sp. ever observed worldwide . BMC Infect Dis 2014 ; 14 : 164 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Papier K , Williams GM, Luceres-Catubig R, et al. . Childhood malnutrition and parasitic helminth interactions . Clin Infect Dis 2014 ; 59 ( 2 ): 234 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Koukounari A , Gabrielli AF, Toure S, et al. . Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso . J Infect Dis 2007 ; 196 ( 5 ): 659 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Mekonnen Z , Meka S, Zeynudin A, et al. . Schistosoma mansoni infection and undernutrition among school age children in Fincha’a sugar estate, rural part of West Ethiopia . BMC Res Notes 2014 ; 7 : 763 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Bustinduy AL , Parraga IM, Thomas CL, et al. . Impact of polyparasitic infections on anemia and undernutrition among Kenyan children living in a Schistosoma haematobium-endemic area . Am J Trop Med Hyg 2013 ; 88 ( 3 ): 433 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Elfaki TE , Arndts K, Wiszniewsky A, et al. . Multivariable regression analysis in Schistosoma mansoni-infected individuals in the Sudan reveals unique immunoepidemiological profiles in uninfected, egg+ and non-egg+ infected individuals . PLoS Negl Trop Dis 2016 ; 10 ( 5 ): e0004629 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Senghor B , Diallo A, Sylla SN, et al. . Prevalence and intensity of urinary schistosomiasis among school children in the district of Niakhar, region of Fatick, Senegal . Parasit Vectors 2014 ; 7 : 5 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Pinot de Moira A , Fulford AJ, Kabatereine NB, et al. . Analysis of complex patterns of human exposure and immunity to Schistosomiasis mansoni: the influence of age, sex, ethnicity and IgE . PLoS Negl Trop Dis 2010 ; 4 ( 9 ): e820 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Geleta S , Alemu A, Getie S, et al. . Prevalence of urinary schistosomiasis and associated risk factors among Abobo Primary School children in Gambella Regional State, southwestern Ethiopia: a cross sectional study . Parasit Vectors 2015 ; 8 : 215 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Robert CF , Bouvier S, Rougemont A. Epidemiology of schistosomiasis in the riverine population of Lagdo Lake, northern Cameroon: mixed infections and ethnic factors . Trop Med Parasitol 1989 ; 40 ( 2 ): 153 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 23 Sow S , de Vlas SJ, Stelma F, et al. . The contribution of water contact behavior to the high Schistosoma mansoni infection rates observed in the Senegal River Basin . BMC Infect Dis 2011 ; 11 : 198 . Google Scholar Crossref Search ADS PubMed WorldCat 24 Benefice E , Luna Monrroy SJ, Lopez Rodriguez RW, et al. . Fat and muscle mass in different groups of pre-pubertal and pubertal rural children. Cross-cultural comparisons between Sahelian (rural Senegal) and Amazonian (Beni River, Bolivia) children . Ann Hum Biol 2011 ; 38 ( 4 ): 500 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 25 Greaves KA , Puhl J, Baranowski T, et al. . Ethnic differences in anthropometric characteristics of young children and their parents . Hum Biol 1989 ; 61 ( 3 ): 459 – 77 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 26 Simondon KB , Ndiaye T, Dia M, et al. . Seasonal variations and trends in weight and arm circumference of non-pregnant rural Senegalese women, 1990–1997 . Eur J Clin Nutr 2008 ; 62 ( 8 ): 997 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 27 Ahima RS , Prabakaran D, Mantzoros C, et al. . Role of leptin in the neuroendocrine response to fasting . Nature 1996 ; 382 ( 6588 ): 250 – 2 . Google Scholar Crossref Search ADS PubMed WorldCat 28 Duggal P , Guo X, Haque R, et al. . A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children . J Clin Invest 2011 ; 121 ( 3 ): 1191 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 29 Potter JJ , Rennie-Tankesley L, Mezey E. Influence of leptin in the development of hepatic fibrosis produced in mice by Schistosoma mansoni infection and by chronic carbon tetrachloride administration . J Hepatol 2003 ; 38 ( 3 ): 281 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 30 Schaible UE , Kaufmann SH. Malnutrition and infection: complex mechanisms and global impacts . PLoS Med 2007 ; 4 ( 5 ): e115 . Google Scholar Crossref Search ADS PubMed WorldCat 31 Gaayeb L , Pincon C, Cames C, et al. . Immune response to Bordetella pertussis is associated with season and undernutrition in Senegalese children . Vaccine 2014 ; 32 ( 27 ): 3431 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 32 Gaayeb L , Sarr JB, Cames C, et al. . Effects of malnutrition on children’s immunity to bacterial antigens in northern Senegal . Am J Trop Med Hyg 2014 ; 90 ( 3 ): 566 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat 33 Falkard B , Uddin T, Rahman MA, et al. . Plasma leptin levels in children hospitalized with cholera in Bangladesh . Am J Trop Med Hyg 2015 ; 93 ( 2 ): 244 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes 1 " Present address: Department of International Affairs, Institut Pasteur, Paris, France 2 " Present address: Institut de Recherche pour le Développement, UMR MIVEGEC, BP 64501, 34394 Montpellier, France © The Author(s) 2018. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected]. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Transactions of The Royal Society of Tropical Medicine and Hygiene Oxford University Press

Sex-dependent interactions between leptin, wasting and humoral immunity in two ethnic communities of school-aged children differentially exposed to Schistosoma haematobium

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Abstract

Abstract Background Leptin is a nutritional hormone whose production is generally higher in females. We investigated how leptin is associated with sex dimorphism during urinary schistosomiasis in relation with wasting. Methods A cross-sectional study was carried out in three villages in northern Senegal. Ninety-eight school-aged children belonging to the Fulani or Wolof villages were enrolled. We performed parasitic diagnosis and anthropometric measurement to evaluate nutritional status. We collected peripheral blood to determine the amount of circulating leptin and immunoglobulin G (IgG), IgG4 and IgE directed to soluble worm antigen preparation (SWAP). Results The prevalence of Schistosoma haematobium infection was higher among boys regardless of ethnic group, but exposure to parasites did not exacerbate malnutrition. The greater ability of girls to produce leptin was not altered by schistosomiasis and was recovered in both ethnic groups. However, while the usual correlation between leptin and fat storage was preserved in Fulani girls, it was disrupted in Fulani boys, who displayed a remarkable susceptibility for wasting. Finally, we observed that leptin was negatively associated with the level of antibodies in Wolof boys. Conclusions Leptin can be disconnected from body fat and may exert a sex-dependent influence on host immune response to S. haematobium infection in Senegalese children. Antibody response, Ethnicity, Leptin, Schistosomiasis, Sex, Wasting Introduction Schistosomiasis is among the most widespread human parasitic diseases, with more than 200 million people infected worldwide and the majority of these infections occurring in sub-Saharan Africa. The two major species are Schistosoma mansoni and Schistosoma haematobium, causing intestinal and urinary schistosomiasis, respectively. Infections with Schistosoma worms have been associated with anaemia, poor nutritional status, cognitive impairment leading to school delays and a decrease in physical fitness.1 A sex-dependent immune profile is observed in Schistosoma-infected adults.2,3 In line with this, a body of evidence suggests that intrinsic host factors may influence susceptibility to infections with parasitic worms according to the host’s sex.4 There is also convincing evidence that the level of malnutrition in children is commonly worse in boys compared with girls,5,6 although others have found similar levels of malnutrition among males and females.7 The extent to which nutritional hormones may mediate sex dimorphism should be considered in order to provide the basis of a link among sex-related infection, malnutrition and immunity. Among the hormones that could be implicated in the crosstalk between sex and nutritional status, the level of serum leptin is consistently higher in girls than boys.8 Leptin is an adipocytokine encoded by the ob gene and is produced by the white adipose tissue. This hormone is a key mediator of energy metabolism and regulates the hypothalamic axis of satiety.9 Its circulating levels are consequently closely related to weight and nutritional disruption. Leptin is also a pro-inflammatory molecule that drives T helper 1 (Th1)-type immunity and impedes the development of the Th2 phenotype.10 Nevertheless, the possibility that leptin mediates immune deficiency during starvation lacks consensus.11,12 To our knowledge, the leptin profile during human schistosomiasis has never been documented. We decided to decipher the sex-dependent regulation of plasma leptin during S. haematobium infection in relation to undernutrition and whether the nutritional hormone is associated with an altered development of host immunoglobulin G (IgG) and IgE antibodies to worm antigens in two rural ethnic groups of school-aged children living in northern Senegal. Materials and methods Study design This cross-sectional study was carried out in October 2011 in three villages of the Podor district located in northern Senegal: Agniam Towguel, Fanaye-Diery and Niandane. Other detailed information regarding the villages has been described elsewhere.13 A total of 125 children from a subcohort of the ‘AnoPalAnoVac’ project (ClinicalTrials.gov, NCT01545115) were initially selected on the basis of their age (6–10 y in October 2011). Ninety-eight children were finally enrolled in the present study. Date of birth was ascertained from vaccination cards or school registers. A standardized questionnaire was completed for each child to collect information on water contact, symptoms of urinary schistosomiasis or previous praziquantel treatment. Children with a malaria episode or haemoglobin <7 g/dL were not included in the cohort for blood collection. Parasitic diagnosis In a preliminary investigation (phase A, see supplementary Table 1), both urine and stool samples were collected from 97 and 95 children, respectively. From each urine sample, 10 mL were filtered and the number of S. haematobium eggs was evaluated by microscopy. S. mansoni infection was detected by the Kato–Katz method using stool samples. Phase B of the study was designed to collect blood for immune analysis. Thirty-eight S. haematobium–infected and 38 uninfected children were included in this second phase of our investigation in which a second stool sample analysis using the Kato–Katz method was performed on S. mansoni–negative children to make sure they are not infected with either form of schistosomiasis. In Niandane, some children have been treated with praziquantel in the last 6 months because this village was included in a national campaign (Supplementary Figure 1). At the end of the current study, all children were dewormed with mebendazole and those found to be positive for schistosomiasis were treated with praziquantel (40 mg/kg body weight). Malaria infection was estimated by microscopic examination of thick blood smears. Serological analysis For analysis of specific antibodies, 3–5 mL of venous blood were collected in heparinized tubes (Becton Dickinson) around noon. Plasma samples were kept at −20°C as 0.15 mL aliquots in 96-well 0.8 mL deep-well storage plates (ABgene, Thermo Scientific, Waltham, MA, USA) until analysis. The serological level of IgG, IgG4 and IgE antibodies to soluble worm antigen preparation (SWAP) from S. mansoni (provided by Mike Doerhoff, University of Nottingham) was evaluated by an in-house enzyme-linked immunosorbent assay (ELISA). Microtitre plates (Nunc, Roskilde, Denmark) were coated with SWAP at a concentration of 5 μg/mL in phosphate-buffered saline (PBS, pH 7.4) and incubated for 2.5 h at 37°C. Plates were then saturated with PBS containing 0.5% gelatin (Merck, Darmstadt, Germany). The sera were diluted to 1/1200 in PBS containing 0.1% Tween-20 for detection of specific IgG and incubated overnight at 4°C. For the detection of anti-SWAP IgG4 or IgE antibodies, sera were diluted to 1:20 in buffer before incubation. Each corresponding biotinylated monoclonal antibody to human Ig isotype (BD Pharmingen, Erembodegem, Belgium) was incubated for 1 h 30 min at 37°C at a 1/2000 dilution for IgG, 1/3000 for IgG4 and 1/1500 for IgE detection. Peroxidase-conjugated streptavidin was then added (Amersham, Les Ulis, France) and colorimetric development was performed with ABTS (2,2′-azino-bis[3-ethylbenzthiazoline-6-sulphonic acid]; Sigma, St. Louis, MO, USA) in 50 mM citrate buffer (pH 4). The absorbance (optical density [OD]) was measured at 405 nm. Individual results were expressed as the ΔOD value: ΔOD=ODx−ODn, where ODx represents the individual OD value in the sera from children and ODn is the mean OD value obtained from a pool of negative controls. The plasmatic concentration of leptin was assayed using a commercial ELISA (R&D Systems, Abingdon, UK) and absorbance read at 450 nm. All ELISA plates were run on an automated washer (ELx405 Select; Biotek, Winooski, VT, USA) and read on an ELx808 microplate reader (Biotek). Anthropometric measurements Anthropometric data were collected by two trained measurers. Weight measurements were recorded using an electronic scale to the nearest 100 g (Tefal, Paris, France). Height measurements were taken twice and the mean value was used for the analysis. Child nutritional indicators, including height for age Z-score (HAZ), weight for age Z-score (WAZ) and body mass index (BMI) for age Z-score (BAZ), were calculated according to the World Health Organization (WHO) 2007 growth standard by using AnthroPlus for children ≥60 months. As this software derives nutritional status information up to 10 years old for WAZ, this indicator was lacking for four children slightly older than 10 y. We used HAZ<−2 to define stunting or chronic malnutrition, WAZ <−2 to define underweight or global malnutrition and BAZ<−2 to define wasting or acute malnutrition. Statistics The mean differences between groups were tested by the Mann–Whitney U-test and χ2 tests were used for categorical variables to compare proportions between groups. Spearman’s rank correlation coefficient was used to check correlation. The Kruskal–Wallis test followed by Dunn’s analysis was used to compare differences among more than two groups, as indicated in the text. All p-values were two-tailed and differences were considered significant for p<0.05. Analyses were performed using GraphPad Prism 5.02 for Microsoft Windows (GraphPad Software, La Jolla, CA, USA). For the multivariate analysis, egg count was transformed into a categorical variable (0, 1 ; 20, ≥20). A logistic regression for ordinal response was used to identify independent predictors of egg count; pairwise interactions were included in the model but none were significant. The proportional odds assumption and log-linearity assumption were verified. Results A total of 98 children ranging in age from 6 to 10 y and living in three different villages in the Senegal River Basin were recruited. The characteristics of the whole population are shown in Table 1. Most of the people living in Niandane belong to the Wolof ethnic group while the populations of Agniam and Fanaye are mainly of Fulani ethnicity. Table 1. Characteristics of the children . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni NS: not significant. aDifferences in the proportion between villages using the χ2 test or mean difference between villages using the Kruskal–Wallis test. Table 1. Characteristics of the children . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni . All villages . Agniam . Fanaye . Niandane . p-Valuea . Boys, % (n) 49.0 (48) 52.9 (8) 53.5 (23) 44.7 (17) NSc Girls, % (n) 51.0 (50) 47.1 (9) 46.5 (20) 55.3 (21) NS Age (y), mean±SD (n) 8.1±1.5 (98) 7.5±1.4 (17) 8.6±1.4 (43) 7.9±1.4 (38) 0.0149 Height (cm), mean±SD (n) 124.3±9.5 (97) 119.8±8.4 (17) 127.3±8.7 (42) 123.0±9.9 (38) 0.0239 Weight (kg), mean±SD (n) 21.5±4.3 (97) 19.5±3.6 (17) 22.6±4.3 (42) 21.2±4.2 (42) 0.0407 S. haematobium–infected children, % (n) 51.6 (97) 52.9 (9/17) 14.3 (6/42) 92.1 (35/38) <0.0001 Egg number/10 mL urine among infected children, mean±SD 20.9±49.7 9.1±12.1 1.3±3.7 47.9±71.2 <0.0001 Children with other parasite infections, n 7 1 solely infected with Ascaris 1 solely infected with S. mansoni 3 co-infected with S. mansoni1 co-infected with Taenia1 solely infected with S. mansoni NS: not significant. aDifferences in the proportion between villages using the χ2 test or mean difference between villages using the Kruskal–Wallis test. Schistosoma infection and sex The overall prevalence of urinary schistosomiasis in terms of the presence of eggs in urine samples was 51.6% in children (Figure 1A). Nearly all children were infected in Niandane (92.1% [n=38]), half of them in Agniam (52.9% [n=17]), while a low prevalence was observed in Fanaye (14.3% [n=42]). In Niandane, three children were co-infected with S. mansoni and one child who tested negative for urinary schistosomiasis was infected with S. mansoni (Table 1). In Fanaye, one child was solely infected by S. mansoni, whereas one Ascaris-infected child negative for schistosomiasis was detected in Agniam. Children were commonly infected with the gastrointestinal protozoa parasite Blastocystis sp.13 but negative for malaria infection. When we categorized schistosomal infection intensity as recommended by the WHO, 20% of children were heavily infected (≥50 eggs/10 mL of urine) in Niandane (mean egg number±SD: 52.0±72.8 [n=35]) as opposed to Fulani villages where infected children displayed a light infection intensity (mean egg number±SD: 13.9±10.4 [n=15]). Nevertheless, there were no statistical differences in the egg burdens between villages (Figure 1B). We can infer that in all likelihood, both greater exposure to the source of contaminated water or a child’s high-risk behaviour were responsible to the differential susceptibility to schistosomiasis (Supplementary Figure 2). For example, there was little access to tap water in Niandane and nearly every Wolof child regularly bathed in irrigation canals or in the river. In contrast, in Fanaye, tap water is available and the river is 1.6 km from the village. Figure 1. Open in new tabDownload slide Analysis of (A) the proportion of S. haematobium–infected children and (B) the egg number detected in urine samples according to village and sex. The number of children is indicated below the figures. In (B), six children from Niandane displayed >200 eggs/10 mL urine. The χ2 test was used to evaluate p-values for proportions (A) and the Mann–Whitney U-test to compare egg counts (B). Figure 1. Open in new tabDownload slide Analysis of (A) the proportion of S. haematobium–infected children and (B) the egg number detected in urine samples according to village and sex. The number of children is indicated below the figures. In (B), six children from Niandane displayed >200 eggs/10 mL urine. The χ2 test was used to evaluate p-values for proportions (A) and the Mann–Whitney U-test to compare egg counts (B). We next considered the risk of sex-dependent parasite transmission after stratification by ethnic groups, which also contributes to distinguish areas of mild (Niandane) and low intensity of infection (Fanaye and Agniam). A trend towards a higher proportion of S. haematobium infection among boys as compared with girls was observed in both the Wolof and Fulani populations, although this did not achieve statistical significance (Figure 1A). However, the mean egg burden/10 mL of urine displayed a similar distribution between boys and girls with schistosomiasis in all villages (Figure 1B). On the basis of these results, we confirm that male sex could be a determinant of transmission risk in Senegalese children while the intensity of infection was sex independent in our study. Nutritional characteristics We assessed nutritional status in children stratified by ethnic group and sex (Table 2). Fulani and Wolof living places were not statistically different with respect to nutritional status. Moreover, we found that the proportion of wasting was worsened and three times higher among Fulani boys (58.6%) as compared with Fulani girls (19.4%; p=0.0018). Conversely, the proportion of wasting among Wolof children living in Niandane did not vary statistically between boys (23.8%) and girls (35.3%; p=0.4376) and both presented a similar mean BAZ. Table 2. Children’s nutritional characteristics . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS aDifference between boys and girls using the Mann–Whitney U-test. bDifference as compared with Fulani boys using the Mann–Whitney U-test. cDifference as compared with Fulani girls using the Mann–Whitney U-test. dp<0.05 when compared with Fulani boys using the χ2 test. Table 2. Children’s nutritional characteristics . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS . Fulani villages . Wolof village . All . Boys . Girls . p-Valuea . All . Boys . Girls . p-Valuea . HAZ, mean±SD −0.50±1.1 −0.39±1.19 −0.61±1.05 NS −0.65±0.90 −0.7±0.97 −0.55±0.81 NS Stunting, % (n) 10.0 (60) 10.3 (29) 9.7 (31) 10.5 (38) 9.5 (21) 11.8 (17) p-Value NSb NSc WAZ, mean±SD −1.39±1.0 −1.44±1.07 −1.33±0.92 NS −1.33±0.82 −1.36±0.96 −1.30±0.65 NS Underweight, % (n) 23.2 (56) 32.1 (28) 14.3 (28) 15.8 (38) 19.1 (21) 11.8 (17) p-Value NS NS BAZ, mean±SD −1.70±0.98 −1.96±0.97 −1.45±0.94 0.0141 −1.43±0.77 −1.40±0.85 −1.47±0.68 NS Wasting, % (n) 38.3 (60) 58.6 (29) 19.4d (31) 28.9 (38) 23.8 (21) 35.3 (17) p-Value 0.0250 NS Leptin, mean±SD (n) 614.9±594.9 (41) 382.2±184.6 (25) 978.±811.1 (16) 0.0050 438.9±327.8 (19) 271.5±67.6 (11) 669.1±406.5 (8) 0.0034 p-Value NS NS aDifference between boys and girls using the Mann–Whitney U-test. bDifference as compared with Fulani boys using the Mann–Whitney U-test. cDifference as compared with Fulani girls using the Mann–Whitney U-test. dp<0.05 when compared with Fulani boys using the χ2 test. We next investigated the relationships between leptin and wasting in our population. As indicated in Table 2, the average concentration of leptin was strongly and significantly lower in boys as compared with girls in both ethnic groups. The amount of serological leptin was well correlated with BAZ in girls but not in boys in the entire population (Figure 2A and B). This sex-relative positive association was particularly more pronounced among Fulani girls (Figure 2D) compared with Fulani boys (Figure 2C), whose level of the nutritional hormone was consistently low regardless of their nutritional status (data not shown). Therefore the clear sex-dependent exacerbation of acute weight loss among boys belonging to Fulani villages was associated with a strong disruption in the link between weight and leptin level. Figure 2. Open in new tabDownload slide Correlation between plasma leptin concentration and BAZ for all villages (A and B; n=36 and n=24, respectively), Fulani villages (C and D; n=25 and n=16, respectively) and the Wolof village (E and F; n=11 and n=8, respectively) among girls and boys as indicated in the figure. The coefficients of correlation and p-values are indicated when significant. The Spearman’s rank correlation coefficient was used to assess correlation. p-Values <0.05 were considered significant. Figure 2. Open in new tabDownload slide Correlation between plasma leptin concentration and BAZ for all villages (A and B; n=36 and n=24, respectively), Fulani villages (C and D; n=25 and n=16, respectively) and the Wolof village (E and F; n=11 and n=8, respectively) among girls and boys as indicated in the figure. The coefficients of correlation and p-values are indicated when significant. The Spearman’s rank correlation coefficient was used to assess correlation. p-Values <0.05 were considered significant. Malnutrition in relation with Schistosoma infection The proportion of stunting, underweight and wasting did not differ between uninfected and Schistosoma-infected children when they were analysed as a whole (data not shown). As nearly all children were infected in Niandane, we then focused our investigation on the relationships between the number of eggs and nutritional parameters in the whole population of Fulani villages that combined both uninfected and Schistosoma-infected children. We found no correlation between mean egg counts and BAZ in both boys (Spearman r=−0.0513, p=0.7916, n=29) and girls (Spearman r=0.0209, p=0.9127, n=30). In contrast, we found that the amount of circulating leptin was positively associated with egg load in Fulani girls (Spearman r=0.5400, p=0.0308, n=16). This correlation was lacking in both Fulani boys (Spearman r=0.1277, p=0.5429, n=25) and among chronically-infected children from Niandane (data not shown). A multivariate analysis was additionally performed to better evaluate the relationships between egg numbers, nutritional status and circulating leptin (Table 3). We confirmed that the village of Niandane and increased leptin concentration can be considered as risk factors for having higher egg numbers. Overall, our data do not support that S. haematobium infection is associated with weight loss in our cohort of Senegalese children. Table 3. Multivariate analysis for evaluating risk factors associated with egg numbers Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 ap-Values <0.05 indicate a significant difference. Table 3. Multivariate analysis for evaluating risk factors associated with egg numbers Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 Variable . OR . 95% CI . p-Valuea . Male sex 3.051 0.795 to 11.719 0.10 Niandane village 20.756 5.455 to 78.972 <0.0001 Leptin (per unit) 1.001 1.000 to 1.003 0.04 Wasting 0.515 0.168 to 1.584 0.25 ap-Values <0.05 indicate a significant difference. Influence of nutritional status on immune responsiveness to Schistosoma antigens We analysed the antibody response to worm antigens in children. As anticipated because of their greater exposure to S. haematobium infection, Wolof children living in Niandane produced a higher mean level of anti-SWAP-specific antibodies than infected Fulani children for all tested isotypes (Figure 3A–C). Even if the level of anti-SWAP IgG antibodies was statistically slightly increased in uninfected girls as compared with uninfected boys, no difference in the amount of specific antibodies was observed between Schistosoma-infected boys and Schistosoma-infected girls (Figure 3D–F). Figure 3. Open in new tabDownload slide Analysis of circulating antibodies against SWAP antigens among S. haematobium–infected (Sh+) or uninfected children (Sh−). Individual’s IgG, IgG4 and IgE responses are shown according to ethnic places (A, B, C) or sex (D, E, F). Thin lines indicate the mean ΔOD. In the Wolof village (Niandane), since the great majority of children were infected, only results from S. haematobium–infected children are shown. The number of children is indicated below the dot plots. The Mann–Whitney U-test was used to evaluate p-values for statistical significance between two groups. *Significant difference when compared with Sh− children; **significant difference when compared with Sh+ children; ***significant difference between uninfected girls and boys. Figure 3. Open in new tabDownload slide Analysis of circulating antibodies against SWAP antigens among S. haematobium–infected (Sh+) or uninfected children (Sh−). Individual’s IgG, IgG4 and IgE responses are shown according to ethnic places (A, B, C) or sex (D, E, F). Thin lines indicate the mean ΔOD. In the Wolof village (Niandane), since the great majority of children were infected, only results from S. haematobium–infected children are shown. The number of children is indicated below the dot plots. The Mann–Whitney U-test was used to evaluate p-values for statistical significance between two groups. *Significant difference when compared with Sh− children; **significant difference when compared with Sh+ children; ***significant difference between uninfected girls and boys. We next assessed whether BAZ and leptin could be associated with variations in humoral immunity to worm infection in children. Because IgE response was not much higher than the baseline serum IgE observed in uninfected children among the Fulani population, we did not further study its relation with nutritional indicators. Table 4 underlines a significant positive association between SWAP-specific IgG antibodies and BAZ among infected Fulani children. A sex-dependent association was observed between BAZ and the level of SWAP-specific IgG4 but we remain cautious about this sex difference because of the low specific IgG4 concentration detected among girls from Fulani villages (four of them displayed an undetectable IgG4 response). More striking results were observed among infected Wolof boys, whose leptin levels seemed to be strongly and negatively associated with the development of antibodies to worm antigens among IgG, IgG4 and to a lesser extent IgE isotypes (p=0.0556; Table 4). Altogether, these results suggest that the nutritional pattern may sex-dependently influence humoral immunity to Schistosoma infection. Table 4. Correlations between nutritional parameters and humoral immunity in infected children Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 NS: not significant. aNon-parametric Spearman’s rank correlation test. Table 4. Correlations between nutritional parameters and humoral immunity in infected children Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 Correlation coefficient (r)a . . BAZ . Leptin . All . Boys . Girls . All . Boys . Girls . Fulani villages Anti-SWAP IgG 0.6179 0.5515 0.8000 0.4643 0.3091 0.8000 0.0141 NS NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Anti-SWAP IgG4 0.2946 0.6485 0.7071 −0.2582 0.0182 0.7071 NS p=0.0425 NS NS NS NS n=15 n=10 n=5 n=15 n=10 n=5 Wolof village Anti-SWAP IgG −0.1300 −0.2909 0.2571 −0.3556 −0.8091 −0.4286 NS NS NS NS p=0.0026 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgG4 0.1177 −0.1093 0.6000 −0.2305 −0.9066 0.0857 NS NS NS NS p=0.0001 NS n=17 n=11 n=6 n=17 n=11 n=6 Anti-SWAP IgE 0.1176 0.1000 0.0286 −0.1250 −0.5909 0.0857 NS NS NS NS NS NS n=17 n=11 n=6 n=17 n=11 n=6 NS: not significant. aNon-parametric Spearman’s rank correlation test. Discussion Schistosomiasis and malnutrition are overlapping in developing countries and both are public health issues. The present work studied how leptin interacts with wasting in children with urinary schistosomiasis in two ethnic communities of Senegalese school-aged children living near the Senegal River. Our data reveal the presence of complex sex-dependent links between nutritional parameters, living places and the development of acquired immunity to Schistosoma antigens. Several studies in Africa have highlighted the contribution of schistosomiasis to the risk of undernutrition in children,6,14 however, these associations have not been consistently observed.15 In Ethiopia, Mekonnen et al.16 documented that infection with S. mansoni was negatively associated with wasting in people 6–18 y of age. Herein, in a younger population, we did not observe that the odds of infection with S. haematobium exert an apparent effect on nutritional status. The number of children in our cohort is quite low and might explain such discrepancies with other works. However, as discussed by Mekonnen et al.,16 harbouring polyparasite infections should be detrimental for childhood growth and development.17 In our cohort in northern Senegal, the absence of filarial infections (no microfilariae detected in blood smears) or soil-transmitted helminthiasis and hookworms in stool underlines a low level of co-infection that could explain the lack of a deleterious effect of schistosomiasis on weight. In addition, sanitary conditions were different between villages and may be responsible for the levels of exposure to Schistosoma worms observed in our work. The educational background can also accentuate the severity of egg burden,18 and we cannot clearly determine whether knowledge about Schistosoma infection delineated differences in the prevalence of the disease between villages. We nevertheless confirmed that sex was significantly associated with Schistosoma infection in school-aged children. Indeed, the overall increased number of S. haematobium–infected males in the studied villages corroborates previous observations in Senegal19 and other African countries.20,21 Indeed, although we must be cautious since our survey did not tightly capture the social and ecological environment of the population, a number of indications have shown that sex-related differences in the distribution of schistosomiasis infection are attributable to social and cultural habits, where water is obtained and variations in cercarial exposure.19,20,22 Additional work also performed in northern Senegal indicated the level of exposure to contaminated water was not related to the intensity of intestinal infection.23 Beyond these statements, the pattern of stronger resistance to schistosomiasis infection among Senegalese girls, which equally occurred in both Fulani and Wolof populations, did stress that being female, combined with extrinsic environmental factors, might cause a difference in susceptibility to worm infection. It is also well accepted that girls generally demonstrate a better nutritional pattern than boys, at least at younger ages.6,24 We further found that the prevalence of wasting was increased in boys, but only in Fulani children, suggesting that ethnic background could have implications for the outcomes of sex-dependent malnutrition. Nonetheless, although ethnic differences in adiposity have been previously observed in a comparative study,25 the difference in the level of wasting between Fulani and Wolof boys must be interpreted with caution, as Fula are known to be taller and slimmer than many of their neighbouring communities. A variation in physical activity, energy expenditure or in dietary intake between boys and girls may additionally account for the higher level of malnourished boys in Fulani villages. It is indeed important to note that our study was performed during the lean season, when low availability of food is generally characterized by a loss of weight, especially among boys.26 In line with this, it could be argued that Senegalese Fulani boys are highly sensitive to environmental insults that may result in worsened acute weight loss as compared with girls. In addition, the usual correlation between leptin and BAZ was disrupted in Wolof children and was sex dependent in Fulani children. The lack of significant correlations between leptin and anthropometric measurements underlines that leptin is not solely a readout of fat stores and that dissociation between circulating leptin and BAZ could likely be a characteristic of a starvation program to adjust energy intake during food shortages or infections.27 It is actually conceivable that leptin could emerge as a main candidate driving sex differences in the susceptibility to parasite infection. It should be noted that experimental infection with intestinal helminths may modulate leptin levels and that leptin signalling can affect resistance to amoebiasis in children.28 In mice infected with S. mansoni, leptin has been indirectly involved in the outcome of hepatic fibrogenesis.29 However, leptin has been poorly investigated in humans with respect to infection in resource-limited areas and, to our knowledge, its role has never been assessed among schistosomiasis-infected patients. We found that ethnicity and schistosomiasis did not influence the well-known ability of girls to produce a greater amount of leptin than boys. Moreover, we found that circulating leptin was significantly linked with egg burden in urine, but a close association between leptin and worm fecundity has not yet been formally demonstrated. Indeed, one limit of our work concerns the two different ethnic communities under study who were differentially exposed to urinary schistosomiasis. As a result, it is difficult to draw any confident conclusion on the ethnic-dependent interactions between different variables. Therefore we cannot assert whether leptin in relation to host immunity potentiates resistance to this parasitic infection. We and others have reported that nutritional deprivation can alter development of the immune response and thereby may confer higher susceptibility to infections.30–32 While the influence of leptin on inflammation and T-cell activation has often been reported,10 few research teams have addressed the role of adipokines on the development of humoral immunity in humans. Although leptin did not consistently sustain the development of specific antibodies to vaccines,11 a recent study has suggested that leptin enhanced humoral immunity to T-cell-dependent antigens during cholera in humans.33 Herein we did not provide strong evidence that wasting negatively affects humoral immunity in Schistosoma-infected children. However, we observed that an increase in leptin concentration seems to reduce the magnitude of antibody response directed towards SWAP antigens in Wolof boys. It is important to note that the disruption between leptin and BAZ in this population strongly indicates that the potent negative effect of leptin on host immunity was independent of fat stores. Taking into account that a sex-dependent modulation of antibody production to Schistosoma species has previously been documented in endemic areas,2,3 our results substantially suggest that leptin may mediate such variations in populations exposed to the infection. Conclusion Our work suggests the complexity of the loop by which the appetite-regulating hormone leptin is engaged in modulating energy balance and adaptive humoral immune response through mechanisms that are probably independent of the child’s weight. Thus some of the sex-related differences observed in diverse endemic fields could be attributed to the underlying interactions between diet, adipokines, seasonal environment and ethnic background during host–parasite relationships. Their influence on the course of schistosomiasis disease remains an important issue to be further clarified. It may be particularly valuable to conduct a study with a multidisciplinary approach in a larger cohort of children to further assess whether leptin could be a critical factor for susceptibility to parasite infections and sex-dependent fitness in sub-Saharan Africa. Supplementary data Supplementary data are available at Transactions online (http://trstmh.oxfordjournals.org/). Authors’ contributions: EH, GR and LG conceived and designed the field study. AS, SS, MS and LG contributed to field activities and clinical examination. AMS, DDG and LB contributed to parasitic diagnostic tests and did the data analysis. PSS, CB and AMS carried out the ELISAs and did the data analysis. EH analysed the data and wrote the manuscript. GR supervised the work. All authors read and approved the final version of the manuscript. EH is the guarantor of the paper. Acknowledgements: We thank Dr Claire Pincon (Faculty of Pharmacy, Lille, France) for her help with the linear regression analysis. We would like to thank the children, families and health care staffs in the visited villages for their kind collaboration as well as the whole EPLS team for their help with the field study. Funding: LG received support from the Region Nord-Pas de Calais and the Pasteur Institute of Lille. EPLS supported the field investigations while the CIIL provided support for immunological assays. Competing interests: none declared. 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes 1 " Present address: Department of International Affairs, Institut Pasteur, Paris, France 2 " Present address: Institut de Recherche pour le Développement, UMR MIVEGEC, BP 64501, 34394 Montpellier, France © The Author(s) 2018. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected].

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Transactions of The Royal Society of Tropical Medicine and Hygiene – Oxford University Press

Published: Oct 1, 2017

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